022567orig1s000 - food and drug administration · 04-nov-2010 was also reviewed. the nda is...

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

022567Orig1s000

CHEMISTRY REVIEW(S)

ONDQA Division Director’s Memo NDA 22-567, VIIBRYD (vilazodone) 10 mg, 20 mg, and 40 mg Tablets Date: 07-JAN-2011 Introduction VIIBRYD (vilazodone) 10 mg, 20 mg, and 40 mg immediate release (IR) film coated (FC) tablets are indicated for the treatment of major depressive disorder. This product should be titrated with an initial dose of 10mg once daily for 7 days followed by 20mg once daily for an additional 7 days. This drug should be taken with food. ONDQA recommends approval of this NDA. Adminstrative The original submission of this 505(b)(1) NDA was received 22-MAR-2010 from PGx Health of New Haven, Connecticut. During the review cycle a CMC amendment dated 04-NOV-2010 was also reviewed. The NDA is supported by IND 54,613 and seven drug master files (DMF). Consults for EES (26-MAY-2010), PharmTox (16-NOV-2010), Biopharm (06-NOV-2010), and DMEPA (for Trade name, 03-NOV-2010) were all acceptable This NDA is recommended for approval from a Chemistry, Manufacturing and Controls standpoint. Drug Substance (vilazodone hydrochloride) Chemical Name: 2-benzofurancarboxamide, 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1- piperazinyl]-, hydrochloride (1:1)

Molecular Formula : C26 H27 N5 O2 x HCl

Molecular Weight : 477.99 (vilazodone HCl) and 441.2 (vilazodone)

The drug substance is a white to cream colored achiral solid manufactured via a The drug substance is . The pKa is

7.1 and the aqueous solubility is 0.32 mg/mL. The assigned retest date for the drug substance is

Reference ID: 2888631

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Drug Product VIIBRYD (vilazodone) 10 mg, 20 mg, and 40 mg Tablets All three strengths are manufactured by

Excipients used in the formulation are conventional and include lactose, microcrystalline cellulose, colloidal silicone dioxide, magnesium stearate and film coating. The film coat varies according to strength:

The HDPE bottles are sized to accommodate 30, 90, or 500 tablets/bottle. Each bottle also contains a 1 gm desiccant canister. The data support the proposed shelf life of 24 months when stored at room temperature. Rik Lostritto, Director, ONDQA Division I, DPAMS


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---------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically and this page is the manifestation of the electronicsignature.---------------------------------------------------------------------------------------------------------/s/----------------------------------------------------

RICHARD T LOSTRITTO01/07/2011


CHEMISTRY REVIEW

NDA 22-567

Vilazodone 10, 20, 40mg Tablets

PGxHealth, LLC

Pei-I Chu, Ph.D. Office of New Drug Quality Assessment DPA1

For Division of Psychiatry Drug Products

Review of Chemistry, Manufacturing, and Controls


CHEMISTRY REVIEW

Table of Contents

Table of Contents ................................................................................................2

Chemistry Review Data Sheet ...........................................................................3

The Executive Summary ....................................................................................7

I. Recommendations................................................................................................................7 A. Recommendation and Conclusion on Approvability................................................................... 7 B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk

Management Steps, if Approvable ............................................................................................... 7

II. Summary of Chemistry Assessments...................................................................................7 A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 7 B. Description of How the Drug Product is Intended to be Used.......................................................... 8 C. Basis for Approvability or Not-Approval Recommendation............................................................ 8

III. Administrative.....................................................................................................................8 A. Reviewer’s Signature........................................................................................................................ 8 B. Endorsement Block........................................................................................................................... 8 C. CC Block .......................................................................................................................................... 9

Chemistry Assessment..................................................................................... 10

I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data.10 S DRUG SUBSTANCE [Name, Manufacturer].......................................................................... 10 P DRUG PRODUCT [Name, Dosage form] ............................................................................... 82 A APPENDICES........................................................................................................................ 137 R REGIONAL INFORMATION............................................................................................... 137

II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ..........................138 A. Labeling & Package Insert .......................................................................................................... 138 B. Environmental Assessment Or Claim Of Categorical Exclusion ................................................. 141


Chemistry Review Data Sheet

Page 3 of 147

CHEMISTRY REVIEW


1. NDA 22-567

2. REVIEW # 1:

3. REVIEW DATE: October 30, 2010

4. REVIEWER: Pei-I Chu, Ph.D.

5. PREVIOUS DOCUMENTS:

Previous Documents Document Date None

6. SUBMISSION(S) BEING REVIEWED:

Submission(s) Reviewed Document Date Original 22-March-2010

7. NAME & ADDRESS OF APPLICANT:

Name: PGx Health

Address: Five Science Park New Haven, CT 06511

Representative: Kimberly Fabrizio

Telephone: 203-786-3502

8. DRUG PRODUCT NAME/CODE/TYPE: N/A

a) Proprietary Name: TBD b) Non-Proprietary Name (USAN): Vilazodone Hydrochloride (vilazodone HCl) c) Code Name/# (ONDC only):N/A d) Chem. Type/Submission Priority (ONDC only):

• Chem. Type: 1 • Submission Priority: S



Page 4 of 147

CHEMISTRY REVIEW

9. LEGAL BASIS FOR SUBMISSION:

505(b)(1)

10. PHARMACOL. CATEGORY: Major Depressive Disorder

11. DOSAGE FORM: Tablet

12. STRENGTH/POTENCY: 10mg, 20mg, 40mg

13. ROUTE OF ADMINISTRATION: Oral

14. Rx/OTC DISPENSED: _X__Rx ___OTC

15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):

SPOTS product – Form Completed X Not a SPOTS product

16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA, MOLECULAR WEIGHT:

Chemical Name: 2-benzofurancarboxamide, 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-

piperazinyl]-, hydrochloride (1:1)

5-{4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl}-benzofuran-2-carboxamide hydrochloride


Molecular Weight : 477.99 (vilazodone HCl)

441.2 (vilazodone)

17. RELATED/SUPPORTING DOCUMENTS:



Page 5 of 147

CHEMISTRY REVIEW

A. DMFs:

1 Action codes for DMF Table:

1 – DMF Reviewed.

Other codes indicate why the DMF was not reviewed, as follows:

2 –Type 1 DMF 3 – Reviewed previously and no revision since last review 4 – Sufficient information in application 5 – Authority to reference not granted 6 – DMF not available 7 – Other (explain under “Comments”)

2 Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did not need to be reviewed)

DMF # TYPE HOLDER ITEM REFERENCED CODE1 STATUS2

DATE REVIEW COMPLETED

COMMENTS

IV

1

Adequate 10/25/2010

III 4

Sufficient info provided

III 1

Adequate 07/07/2010

III 4


III 4


III 4


III 4 Sufficient info provided


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Page 6 of 147

CHEMISTRY REVIEW

I. B. Other Documents: DOCUMENT APPLICATION

NUMBER DESCRIPTION

IND 54613 Commercial IND

18. STATUS:

ONDC: CONSULTS/

CMC RELATED REVIEWS

RECOMMENDATION DATE REVIEWER

Biometrics NA EES acceptable 5/26/2010 OC Pharm/Tox Pending (waiting for IR

response) 10/16/2010 Violetta Klimek

Biopharm Pending (waiting for IR response)

10/16/2010 Tien Min Chen

LNC NA Methods Validation NA

OPDRA NA DMEPA NA EA NA Microbiology NA


Chemistry Review Section

Page 7 of 147

CHEMISTRY REVIEW

The Chemistry Review for NDA 22-567

The Executive Summary I. Recommendations A. Recommendation and Conclusion on Approvability

NDA 22567 is recommended approvable from the CMC standpoint. The approval is contingent upon satisfactory

response from the applicant on the drug substance and drug product questions. A summary of CMC questions is listed at the end of this review. Office of compliance has determined that pre-approval inspections for the drug substance, drug product and packaging sites are not needed based on profile.

B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk Management Steps, if Approvable None as per this review. II. Summary of Chemistry Assessments A. Description of the Drug Product(s) and Drug Substance(s)

Vilazodone HCl is a dual-acting and selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist. It is thought to optimize regulation of 5-HT circuitry at both pre- and postsynaptic sites to augment 5-HT neurotransmission, thereby producing an antidepressant effect. Its clinical indication is for the treatment of major depressive disorder. Vilazodone HCl is a new chemical entity belonging to the structural chemical group of the indolalkylamines. The full chemical designation is 2-benzofurancarboxamide, 5-[4-[4-(5-cyano- 1H-indol-3-yl)butyl]-1-piperazinyl]-, hydrochloride (1:1)

Vilazodone HCl drug substance is a white to cream-colored solid. It is achiral and slightly hygroscopic. Solid state form analysis demonstrates that it exists in multiple polymorphs ). form IV was chosen for development. The solubility in water is 0.32mg/mL. The partition coefficient between n-octanol and water is

The pKa is 7.1. The melting point and decomposition starts at ~270ºC.

Vilazodone HCl is manufactured, by:

ScinoPharm Taiwan, Ltd. (SPT) in Shan-Hua, Taiwan, R.O.C. The drug substance is manufactured in a A typical batch yield is from . The resulting drug substance is

Seven batches of vilazodone HCl manufactured by ScinoPharm Taiwan, Ltd. (SPT) are being evaluated on stability. Three batches were manufactured using the intended commercial process. All batches were packaged in the container closure intended for commercial material. The initial submission included 9 months stability at 25°C/60%RH or for up to 6 months at 40°C/75%RH. 12 month stability data from the development batches has been provided at the mid cycle review period. No significant changes or trends have been observed. However, the firm has only provided two 6 month stability data under accelerated storage of 40°C/75% RH and 25°C/60%RH using the commercial manufacturing process. The assigned re-test date for the drug substance at this point is When additional stability data is provided, the re-test will be re-assessed.


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Page 8 of 147

CHEMISTRY REVIEW

Vilazodone HCl Tablets, 10 mg, 20 mg and 40 mg are immediate-release, oval, film-coated, tablets, manufactured from a with total tablet weights of 103 mg, 206 mg and 412 mg, respectively. The 10 mg tablets are pink; the 20 mg, orange; and the 40 mg, blue. The tablets are debossed with the strength on one side and plain on the other. The tablets are packaged in appropriately-sized, 30-count, 90-count and 500-count high-density polyethylene (HDPE) bottles, and in film/aluminum foil blisters. The drug product will be manufactured by Patheon Puerto Rico, Inc. (Manati, Puerto Rico). Vilazodone HCl Tablets, 10 mg, 20 mg and 40 mg are manufactured from a process using standard techniques, equipment and controls. Manufacturing comprises of

Excipients used in the formulation include lactose, microcrystalline cellulose, colloidal silicone dioxide, magnesium stearate and film coating.

The batch formula for a commercial scale batch is for the 10mg, 20mg and 40mg tablets,

which would results in 10mg tablets, 20mg tablets or 40mg tablets. Vilazodone HCl tablets may be stored in bulk prior to packaging to accommodate for packaging schedule. The HDPE bottles are sized to accommodate 30, 90, or 500 tablets/bottle. Each bottle also contains a 1-g desiccant canister. The applicant has submitted 18 month stability data for 6 batches using drug substance manufactured by Merck (three each of 10mg and 40mg tablets) and 12 month stability data of drug product manufactured with API from Scino Pharm. Based on real time and accelerated stability data at the ICH conditions, the 10mg and 40mg tablets are considered stable under proposed storage container closure systems. Tablets manufactured with API from SPT have the same stability as those manufactured with API from Merck based on comparison of 12-month stability data for SPT-API tablets and Merck-API tablets. The data support the proposed shelf life of 24 months when stored at room temperature.

B. Description of How the Drug Product is Intended to be Used

This product should be titrated with an initial dose of 10mg once daily for 7 days followed by 20mg once daily for an additional 7 days. Vilazodone HCl should be taken with food.

C. Basis for Approvability or Not-Approval Recommendation

The final approval of this NDA will be based on adequate responses to the Information Request sent to PGx Health Care on October 15, 2010.

III. Administrative A. Reviewer’s Signature Endorsement Block Chemist Name: Pei-I Chu, Ph.D./Date: Same date as draft review Chemistry CMC Lead:Tom Oliver, Ph.D./Date Chemistry Branch Chief Ramesh Sood, Ph.D. Chemistry Project Manager Teshara Bouie/Date


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Page 9 of 147

CHEMISTRY REVIEW

C. CC Block Orig. NDA-22-567


138 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page

X


PEI-I CHU11/03/2010

RAMESH K SOOD11/03/2010


CHEMISTRY REVIEW

NDA 22-567

Vilazodone 10, 20, 40mg Tablets

PGxHealth, LLC

Pei-I Chu, Ph.D. Office of New Drug Quality Assessment DPA1

For Division of Psychiatry Drug Products

Review of Chemistry, Manufacturing, and Controls


CHEMISTRY REVIEW

Table of Contents

Table of Contents ................................................................................................2

Chemistry Review Data Sheet ...........................................................................3

The Executive Summary ....................................................................................7

I. Recommendations................................................................................................................7 A. Recommendation and Conclusion on Approvability................................................................... 7 B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk

Management Steps, if Approvable ............................................................................................... 7

II. Summary of Chemistry Assessments...................................................................................7 A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 7 B. Description of How the Drug Product is Intended to be Used.......................................................... 9 C. Basis for Approvability or Not-Approval Recommendation............................................................ 9

III. Administrative.....................................................................................................................9 A. Reviewer’s Signature........................................................................................................................ 9 B. Endorsement Block........................................................................................................................... 9 C. CC Block .......................................................................................................................................... 9

Chemistry Assessment......................................................................................10

I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data.10 S DRUG SUBSTANCE [Name, Manufacturer].......................................................................... 10 P DRUG PRODUCT [Name, Dosage form] ............................................................................... 24 A APPENDICES...........................................................................................................................28 R REGIONAL INFORMATION................................................................................................. 37

II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ............................38 A. Labeling & Package Insert ............................................................................................................ 38 B. Environmental Assessment Or Claim Of Categorical Exclusion ................................................... 38



Page 3 of 38

CHEMISTRY REVIEW


1. NDA 22-567

2. REVIEW # 2:

3. REVIEW DATE: November 30, 2010

4. REVIEWER: Pei-I Chu, Ph.D.

5. PREVIOUS DOCUMENTS:

Previous Documents Document Date None

6. SUBMISSION(S) BEING REVIEWED:

Submission(s) Reviewed Document Date Original Amendment 17-Quality Response to IR

22-March-2010 04-November-2010

7. NAME & ADDRESS OF APPLICANT:

Name: PGx Health

Address: Five Science Park New Haven, CT 06511

Representative: Kimberly Fabrizio

Telephone: 203-786-3502

8. DRUG PRODUCT NAME/CODE/TYPE: N/A

a) Proprietary Name: Viibryd b) Non-Proprietary Name (USAN): Vilazodone Hydrochloride (vilazodone HCl) c) Code Name/# (ONDC only):N/A d) Chem. Type/Submission Priority (ONDC only): • Chem. Type: 1 • Submission Priority: S



Page 4 of 38

CHEMISTRY REVIEW

9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)

10. PHARMACOL. CATEGORY: Major Depressive Disorder

11. DOSAGE FORM: Tablet

12. STRENGTH/POTENCY: 10mg, 20mg, 40mg

13. ROUTE OF ADMINISTRATION: Oral

14. Rx/OTC DISPENSED: _X__Rx ___OTC

15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):

SPOTS product – Form Completed X Not a SPOTS product

16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA, MOLECULAR WEIGHT:

Chemical Name: 2-benzofurancarboxamide, 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-

piperazinyl]-, hydrochloride (1:1)

5-{4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl}-benzofuran-2-carboxamide hydrochloride


Molecular Weight : 477.99 (vilazodone HCl)

441.2 (vilazodone)

17. RELATED/SUPPORTING DOCUMENTS:



Page 5 of 38

CHEMISTRY REVIEW

A. DMFs:

1 Action codes for DMF Table:

1 – DMF Reviewed.

Other codes indicate why the DMF was not reviewed, as follows:

2 –Type 1 DMF 3 – Reviewed previously and no revision since last review 4 – Sufficient information in application 5 – Authority to reference not granted 6 – DMF not available 7 – Other (explain under “Comments”)

2 Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did not need to be reviewed)

DMF # TYPE HOLDER ITEM REFERENCED CODE1 STATUS2

DATE REVIEW COMPLETED

COMMENTS

IV

1

Adequate 10/25/2010

III 4


III 1

Adequate 07/07/2010

III 4


III 4


III 4


III 4 Sufficient info provided


(b) (4) (b) (4)


Page 6 of 38

CHEMISTRY REVIEW

B. Other Documents: DOCUMENT APPLICATION

NUMBER DESCRIPTION

IND 54613 Commercial IND

18. STATUS:

CONSULTS/

CMC RELATED REVIEWS

RECOMMENDATION DATE REVIEWER

Biometrics NA --- --- EES acceptable 5/26/2010 Office of compliance Pharm/Tox acceptable 11/16/2010 Violetta Klimek Biopharm acceptable 11/06/2010 Tien Min Chen LNC NA --- ---

Methods Validation NA --- --- OPDRA NA --- --- DMEPA Viibryd 11/03/2010 Loretta Holmes EA NA --- --- Microbiology NA --- ---



Page 7 of 38

CHEMISTRY REVIEW

The Chemistry Review for NDA 22-567 The Executive Summary

I. Recommendations

A. Recommendation and Conclusion on Approvability

NDA 22567 is recommended approval from the perspective of chemistry, manufacturing, and controls. . An information request letter was sent to the applicant on October 15, 2010. An amendment dated November 04, 2010 included adequate quality responses to the CMC issues. The response to the genotoxic impurities is found adequate by the Pharmatox reviewer. The biopharm reviewer has also determined that the response to the question on dissolution method and dissolution data is adequate. All CMC issues have now been adequately resolved.

Office of compliance has determined the drug substance, drug product and packaging facilities are adequate. Pre-approval inspections for the drug substance, drug product and packaging sites are not needed based on profile.

The sponsor has committed to the following actions in the first NDA annual report:

• Provide a revised validation report to demonstrate the limit of quantitation for Form IV

• Include an updated dissolution method validation report using a stability indicating analytical method.

B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk Management Steps, if Approvable None as per this review. II. Summary of Chemistry Assessments A. Description of the Drug Product(s) and Drug Substance(s)

Vilazodone HCl is a dual-acting and selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist. It is thought to optimize regulation of 5-HT circuitry at both pre- and postsynaptic sites to augment 5-HT neurotransmission, thereby producing an antidepressant effect. Its clinical indication is for the treatment of major depressive disorder. Vilazodone HCl is a new chemical entity belonging to the structural chemical group of the indolalkylamines. The full chemical designation is 2-benzofurancarboxamide, 5-[4-[4-(5-cyano- 1H-indol-3-yl)butyl]-1-piperazinyl]-, hydrochloride (1:1)


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Page 8 of 38

CHEMISTRY REVIEW

Vilazodone HCl drug substance is a white to cream-colored solid. It is achiral and slightly hygroscopic. Solid state form analysis demonstrates that it exists in multiple polymorphs

form IV was chosen for development. The solubility in water is 0.32mg/mL. The partition coefficient between n-octanol and water is . The pKa is 7.1. The melting point and decomposition starts at ~270ºC.

Vilazodone HCl is manufactured, by

ScinoPharm Taiwan, Ltd. (SPT) in Shan-Hua, Taiwan, R.O.C. The drug substance is manufactured in a A typical batch yield is from . The resulting drug substance is

The drug substance is

Seven batches of vilazodone HCl manufactured by ScinoPharm Taiwan, Ltd. (SPT) are being evaluated on stability. Three batches were manufactured using the intended commercial process. All batches were packaged in the container closure intended for commercial material. In the IR response dated November 4, 2010, the applicant has committed to provide a revised validation report to include data in the first NDA annual report. The initial submission included 9 months drug substance stability data at 25°C/60%RH or for up to 6 months at 40°C/75%RH. 12 month stability data from the development batches has been provided at the mid cycle review period. No significant changes or trends have been observed. However, the firm has only provided two 6 month stability data under accelerated storage of 40°C/75% RH and 25°C/60%RH using the commercial manufacturing process. The assigned re-test date for the drug substance at this point is . When additional stability data is provided, the re-test will be re-assessed. Vilazodone HCl Tablets, 10 mg, 20 mg and 40 mg are immediate-release, oval, film-coated, tablets, manufactured from a with total tablet weights of 103 mg, 206 mg and 412 mg, respectively. The 10 mg tablets are pink; the 20 mg, orange; and the 40 mg, blue. The tablets are debossed with the strength on one side and plain on the other. The tablets are packaged in appropriately-sized, 30-count, 90-count and 500-count high-density polyethylene (HDPE) bottles, and in film/aluminum foil blisters. The drug product will be manufactured by Patheon Puerto Rico, Inc. (Manati, Puerto Rico). Vilazodone HCl Tablets, 10 mg, 20 mg and 40 mg are manufactured from a

process using standard techniques, equipment and controls. Manufacturing comprises of

Excipients used in the formulation include lactose, microcrystalline cellulose, colloidal silicone dioxide, magnesium stearate and film coating. The film coat is comprised of:

The batch formula for a commercial scale batch is for the


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Page 9 of 38

CHEMISTRY REVIEW

10mg, 20mg and 40mg tablets, which would results in 10mg tablets, 20mg tablets or 40mg tablets. Vilazodone HCl tablets may be stored in bulk prior to packaging to accommodate for packaging schedule. The HDPE bottles are sized to accommodate 30, 90, or 500 tablets/bottle. Each bottle also contains a 1-g desiccant canister. The applicant has submitted 18 month stability data for 6 batches using drug substance manufactured by Merck (three each of 10mg and 40mg tablets) and 12 month stability data of drug product manufactured with API from Scino Pharm. Based on real time and accelerated stability data at the ICH conditions, the 10mg and 40mg tablets are considered stable under proposed storage container closure systems. Tablets manufactured with API from SPT have the same stability as those manufactured with API from Merck based on comparison of 12-month stability data for SPT-API tablets and Merck-API tablets. The data support the proposed shelf life of 24 months when stored at room temperature. B. Description of How the Drug Product is Intended to be Used

This product should be titrated with an initial dose of 10mg once daily for 7 days followed by 20mg once daily for an additional 7 days. Vilazodone HCl should be taken with food.

C. Basis for Approvability or Not-Approval Recommendation

This NDA (22-567) is recommended for APPROVAL from the perspective of chemistry, manufacturing, and controls. All deficiencies have been adequately resolved.

II. Administrative

A. Reviewer’s Signature

Pei-I Chu, Ph.D. Endorsement Block

Chemist Name: Pei-I Chu, Ph.D. Chemistry CMC Lead: Tom Oliver, Ph.D. Chemistry Branch Chief : Ramesh Sood, Ph.D. Chemistry Project Manager : Teshara Bouie C. CC Block

Orig. NDA-22-567


29 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page

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PEI-I CHU12/06/2010



PRODUCT QUALITY (Small Molecule) FILING REVIEW FOR NDA or Supplement (ONDQA)

File name: 090513-Product Quality Filing Review.doc Page 1 Version Date: 05132009

NDA Number: 22567 Supplement Number and Type: Original

Established/Proper Name: Vilazodone HCl tablets

Applicant:

Letter Date:22-March-2010 Stamp Date: 22-March-2010

The following parameters are necessary in order to initiate a full review, i.e., complete enough to review but may have deficiencies. On initial overview of the NDA application for filing:

A. GENERAL Parameter Yes No Comment

1. Is the CMC section organized adequately? X

2. Is the CMC section indexed and paginated (including all PDF files) adequately?

X

3. Are all the pages in the CMC section legible? X

4.

Has all information requested during the IND phase, and at the pre-NDA meetings been included?

X

B. FACILITIES*

Parameter Yes No Comment

5. Is a single, comprehensive list of all involved facilities available in one location in the application?

x

6.

For a naturally-derived API only, are the facilities responsible for critical intermediate or crude API manufacturing, or performing upstream steps, specified in the application? If not, has a justification been provided for this omission? This question is not applicable for API.

Not Applicable

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7.

Are drug substance manufacturing sites identified on FDA Form 356h or associated continuation sheet? For each site, does the application list: • Name of facility, • Full address of facility including

street, city, state, country • FEI number for facility (if

previously registered with FDA) • Full name and title, telephone, fax

number and email for on-site contact person.

• Is the manufacturing responsibility and function identified for each facility?, and

• DMF number (if applicable)

X

8.

Are drug product manufacturing sites are identified on FDA Form 356h or associated continuation sheet. For each site, does the application list: • Name of facility, • Full address of facility including






X



9.

Are additional manufacturing, packaging and control/testing laboratory sites are identified on FDA Form 356h or associated continuation sheet. For each site, does the application list: • Name of facility, • Full address of facility including






X

10.

Is a statement provided that all facilities are ready for GMP inspection at the time of submission?

X

* If any information regarding the facilities is omitted, this should be addressed ASAP with the applicant and can be a potential filing issue or a potential review issue.

C. ENVIRONMENTAL ASSESMENT


11. Has an environmental assessment report or categorical exclusion been provided?

X



D. DRUG SUBSTANCE/ACTIVE PHARMACEUTICAL INGREDIENT (DS/API) Parameter Yes No Comment

12. Does the section contain a description of the DS manufacturing process?

X

13.

Does the section contain identification and controls of critical steps and intermediates of the DS?

X

14. Does the section contain information regarding the characterization of the DS?

X

15. Does the section contain controls for the DS? X

16. Has stability data and analysis been provided for the drug substance?

X

17. Does the application contain Quality by Design (QbD) information regarding the DS?

X

18.

Does the application contain Process Analytical Technology (PAT) information regarding the DS?

X

Answers to Questions 12-18 are based on information contained within DMF



E. DRUG PRODUCT (DP) Parameter Yes No Comment

19.

Is there a description of manufacturing process and methods for DP production through finishing, including formulation, filling, labeling and packaging?

X

20.

Does the section contain identification and controls of critical steps and intermediates of the DP, including analytical procedures and method validation reports for assay and related substances if applicable?

X

21. Is there a batch production record and a proposed master batch record?

X

22.

Has an investigational formulations section been provided? Is there adequate linkage between the investigational product and the proposed marketed product?

X

23. Have any biowaivers been requested? X

24.

Does the section contain description of to-be-marketed container/closure system and presentations)?

X

25. Does the section contain controls of the final drug product? X

26. Has stability data and analysis been provided to support the requested expiration date?

X

27. Does the application contain Quality by Design (QbD) information regarding the DP?

X

28.

Does the application contain Process Analytical Technology (PAT) information regarding the DP?

X



F. METHODS VALIDATION (MV)


29. Is there a methods validation package? X

G. MICROBIOLOGY


30.

If appropriate, is a separate microbiological section included assuring sterility of the drug product?

Not applicable

H. MASTER FILES (DMF/MAF)


31.

Is information for critical DMF references (i.e., for drug substance and important packaging components for non-solid-oral drug products) complete?

X

DMF # TYPE HOLDER ITEM REFERENCED LOA DATE COMMENTS

I. LABELING


32. Has the draft package insert been provided? X

33. Have the immediate container and carton labels been provided? X



APPEARS THIS WAY ON ORIGINAL.



J. FILING CONCLUSION


34.

IS THE PRODUCT QUALITY SECTION OF

THE APPLICATION FILEABLE?

X

35.

If the NDA is not fileable from the product quality perspective, state the reasons and provide filing comments to be sent to the Applicant.

Not Applicable

36. Are there any potential review issues to be forwarded to the Applicant for the 74-day letter?

Not Applicable

{See appended electronic signature page}

Name of Pharmaceutical Assessment Lead or CMC Lead / CMC Reviewer Date Division of Pre-Marketing Assessment # Office of New Drug Quality Assessment

{See appended electronic signature page}

Name of Branch Chief Date Division of Pre-Marketing Assessment # Office of New Drug Quality Assessment

ApplicationType/Number

SubmissionType/Number Submitter Name Product Name

-------------------- -------------------- -------------------- ------------------------------------------NDA-22567 ORIG-1 PGXHEALTH LLC VILAZODONE HCL


PEI-I CHU05/05/2010


Initial Quality Assessment Branch I OND Division: Division of Psychiatry Products NDA: 22-567 Applicant: PGxHealth, LLC Letter Date: 22-MAR-10 Stamp Date: 22-MAR-10 PDUFA Date: 22-JAN-11 Trademark: Tradename has not been proposed

Established Name: vilazodone hydrochloride Dosage Form: 10, 20, and 40 mg Tablets

Route of Administration: Oral Indication: Major Depressive Disorder

Assessed by: Thomas F. Oliver, Ph.D. Summary Vilazodone, a dual-acting potent and selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist, is indicated for the treatment of major depressive disorder. It was developed under IND 54,613. The applicant had an EOP2 meeting (December 20, 2005) but there were no specific CMC questions. The applicant had a CMC pre-NDA meeting (September 29, 2009) where the following CMC issues were discussed: starting material designation, residual solvent testing , drug substance stability data, drug substance overage in DP, dissolution specification, and drug product stability data. Minutes for both meetings can be found in DARTS and should be read by the reviewer. Drug Substance Vilazodone HCl is achiral and appears as a white to cream-colored solid. Vilazodone HCl is slightly hygroscopic and can exist in multiple polymorphs

Form IV has been chosen for commercial development. Solubility in water is 0.32 mg/mL (20oC). The drug substance will be manufactured by ScinoPharm Taiwan, Ltd. (Shan-Hua, Taiwan). Vilazodone HCl is manufactured in a . Vilazodone HCl is

. The applicant

has assigned a retest date. Seven batches of vilazodone HCl manufactured by ScinoPharm Taiwan, Ltd. (SPT), the intended supplier of commercial material are being evaluated on stability. Three batches were manufactured using the intended commercial process. Four batches were manufactured using a modified commercial process, which differs from the commercial process only

All batches were packaged in the container closure intended for commercial drug substance. Drug Product Vilazodone HCl tablets will be available in 10, 20, and 40 mg strengths. The recommended dose for Vilazodone HCl is 40 mg once daily. Vilazodone HCl should be titrated, starting with an initial dose of 10 mg once daily for 7 days followed by 20 mg once daily for an additional 7 days. Vilazodone HCl should be taken with food.

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2Vilazodone HCl Tablets are immediate-release, oval, film-coated, tablets, manufactured from a . The 10 mg tablets are pink; the 20 mg, orange; and the 40 mg, blue. The tablets are debossed with the strength on one side and plain on the other. The tablet cores are comprised of: vilazodone HCl, microcrystalline cellulose, lactose monohydrate, magnesium stearate, and colloidal silicon dioxide. The film coat is comprised of:

The drug product will be manufactured by Patheon Puerto Rico, Inc. (Manati, Puerto Rico). Vilazodone HCl Tablets, 10 mg, 20 mg and 40 mg are manufactured from a

The batch formula for the commercial scale batches is for the 10mg, 20 mg and 40 mg tablets, which would result in (10 mg), (20 mg) and (40 mg) tablets. Vilazodone HCl tablets may be stored in bulk prior to packaging to accommodate manufacturing schedules. For this interim storage, bulk Vilazodone HCl Tablets are

Two container closure systems (bottles and

blisters) will be used for packaging of commercial vilazodone HCl Tablets. The bottles are high density polyethylene (HDPE), sealed with closures with inner seals. The bottles are sized to accommodate 30, 90, or 500 tablets/bottle. Each bottle also contains a 1-g desiccant canister. The blisters are formed using blister film and aluminum foil blister lidding. The tablets are also supplied in a Patient Starter Kit (blister card containing seven 10 mg tablets, seven 20 mg tablets, and sixteen 40 mg tablets). The sponsor submitted 12-month data for six batches (three each of 10 mg and 40 mg tablets) of primary stability data. The applicant has requested a 24 month expiry for vilazodone HCl tablets. Critical Issues for Review · The applicant states that the drug substance can exist in multiple polymorphic forms

have been observed). Form IV has been chosen for commercial development. It will need to be determined whether the applicant has adequately characterized the various polymorphs and determined the different properties (e.g., solubility, stability) of each form [refer to ICH Q6a]. The applicant tests for the correct solid state form as part of the release and stability testing. It will need to be determined whether the control for Form IV is acceptable (e.g., can small amounts of the other potential polymorphic forms be detected by the analytical solid state method). · Characterization data will need to be evaluated to determine if the data are consistent with the proposed structure of vilazodone HCl. · Six impurities with genotoxic structure alerts are controlled at the

for improved analytical method sensitivity. These are:

It will need to be determined the adequacy of this specification limits and the acceptability of the test method.

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3

· The applicant lists the impurity as a potential genotoxic impurity, which could be formed from

An acceptance specification limit was set at as part of the drug substance specification. It will need to be determined the adequacy of this specification limit and the acceptability of the GC test method. · The applicant has proposed a residual solvent limit for (Option 2) as part of the drug substance release testing. It will need to be the determined the adequacy of the specification limit and method for controlling · Vilazodone HCl is The applicant has proposed a particle size distribution specification Graphical depiction of the particle size distribution should be provided. It should be noted there currently isn’t a control. It will need to be determined whether particle size used in the clinical batches supports the proposed commercial specification and whether a control is needed. It will also need to be determined whether

. The amount of material will need to be determined and the reviewer will need to ensure it is properly controlled. · The applicant has proposed that if vilazodone HCl does not meet the drug substance specification,

The reviewer will need to evaluate the procedure outlined by the applicant and determine the acceptability . · The is used in Step 1 in the

is used as a It will need to be determined whether the applicant has adequate controls for residual levels of . · The compatibility of the drug product excipients will need to be evaluated. · The applicant states that the physicochemical properties of the excipients can influence the manufacturability and performance of the drug product.

It will need to be determined whether the applicant has adequate controls for each of the excipients. · The applicant has developed a number of drug product formulations [

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4 throughout development. The commercial formulation is PG-

10/PG-20/PG-40. The adequacy of this formulation will need to be determined in terms of clinical performance, manufacturability, and stability. · Laboratory-scale experiments led to the conclusion that the best results are obtained by making

· The applicant states that the drug substance can exist in multiple polymorphic forms (

. Form IV has been chosen for commercial development. It will need to be evaluated whether the drug product manufacturing process converts Form IV to one of the other forms. The sponsor does not monitor for the correct polymorphic form as part of the current drug product release or stability testing. It will need to be determined whether this approach is acceptable (refer to ICH Q6a). · The applicant states that the batch formulas for commercial Vilazodone HCl Tablets, 10 mg, 20 mg and 40 mg include a overage of vilazodone HCl API to compensate for loss during tablet manufacture. It will need to be determined whether there is adequate justification for this overage. · Four processes were evaluated (Process I, II, III, and IV). It will need to be determined whether the various modifications have corrected the associated problems. The performance of the commercial product will need to be linked to the performance of the clinically studied product (e.g., formulation, manufacturing process, packaging, stability). ·Vilazodone HCl Tablets, 10 mg, 20 mg and 40 mg are manufactured by a

· Vilazodone HCl tablets (film-coated) are differentiated by color, size, and debossing [with strength debossed on one side and plain on the other]. Samples will need to be requested and the acceptability of the appearance specification will need to be evaluated.

· The applicant has proposed a drug product specification limit of It will need to be determined how that upper limit has been justified (i.e., stability data demonstrating product with is chemically and physically stable and delivers active as outlined in labeling). · The applicant states that vilazodone HCl tablets may be stored in bulk. For this interim storage, bulk Vilazodone HCl Tablets are

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5 It will need to be determined how long tablets

will be stored in bulk packaging before being packaged into the commercial presentations and whether there is adequate data to support this hold (refer to ICH Q7). · Vilazodone HCl Tablets are packaged in of high density polyethylene (HDPE) bottles sealed with either

. All closures have tamper-evident, inner seals. All bottles are packed with 1-g desiccant canisters. It will need to be determined how the sponsor calculated the adequate amount of desiccant to be used. Stability data (long term, accelerated, stress) will need to be evaluated to determine the container-closure offers adequate protection. · The applicant performed photostability testing of the tablets. The reviewer will need to determine whether all types of packaging bottles, blisters) offer adequate protection. In particular, the effect of light on the fading of the tablet color [10 mg/pink; 20 mg/orange; 40 mg/blue] will need to be evaluated. It will need to be determined whether any statement is needed in labeling about the effects of light on the tablets. · The applicant has proposed an expiry of 24 months. The primary drug product stability batches were manufactured using drug substance from Merck KGaA, Darmstadt, Germany. The supplier for commercial drug substance is ScinoPharm Taiwan, Ltd. (SPT). The applicant has compared drug substance manufactured by SCT and Merck and drug product using the respective sourced drug substance. It will need to be determined whether there are any differences in drug product sourced with the different drug substance suppliers. · It appears the dose strengths (10, 20, and 40 mg vilazodone HCl) are correctly labeled as 10, 20, and 40 mg in the HCl label. Reviewer will need to confirm. Comments and Recommendation: The NDA appears to be fileable from a CMC perspective. My recommendation would be for a single reviewer to be assigned to the NDA. As Dr. Thomas Wong was involved in the previous CMC meeting, he would be a prudent choice for reviewer. The applicant claims a categorical exclusion from the requirement to prepare an environmental assessment under 21 CFR § 25.31(b) as the expected introduction concentration (EIC) of

in the aquatic environment is below 1 parts per billion and states that to the applicant’s knowledge, no extraordinary circumstances exist that would warrant the preparation of an environmental assessment. The manufacturing, testing, and packaging sites will need to be submitted into EES (by the ONDQA PM), however, the reviewer will need to confirm that these sites are correct and that there are no additional sites that need to be entered.

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ApplicationType/Number

SubmissionType/Number Submitter Name Product Name

-------------------- -------------------- -------------------- ------------------------------------------NDA-22567 ORIG-1 PGX HEALTH LLC VILAZODONE HCL


THOMAS F OLIVER04/14/2010
